tbuckley/cabot-search huggingface dataset:
A Sequential Targeting Strategy Interrupts AKT-Driven Subclone-Mediated Progression in Glioblastoma
Authors: Sied Kebir, Vivien Ullrich, Pia Berger, Celia Dobersalske, Sarah Langer, Laurèl Rauschenbach, Daniel Trageser, Andreas Till, Franziska K. Lorbeer, Anja Wieland, Timo Wilhelm-Buchstab, Ashar Ahmad, Holger Fröhlich, Igor Cima, Shruthi Prasad, Johann Matschke, Verena Jendrossek, Marc Remke, Barbara M. Grüner, Alexander Roesch, Jens T. Siveke, Christel Herold-Mende, Tobias Blau, Kathy Keyvani, Frank K.H. van Landeghem, Torsten Pietsch, Jörg Felsberg, Guido Reifenberger, Michael Weller, Ulrich Sure, Oliver Brüstle, Matthias Simon, Martin Glas, Björn Scheffler
Journal: Clinical Cancer Research (2022)

Abstract Purpose: Therapy resistance and fatal disease progression in glioblastoma are thought to result from the dynamics of intra-tumor heterogeneity. This study aimed at identifying and molecularly targeting tumor cells that can survive, adapt, and subclonally expand under primary therapy. Experimental Design: To identify candidate markers and to experimentally access dynamics of subclonal progression in glioblastoma, we established a discovery cohort of paired vital cell samples obtained before and after primary therapy. We further used two independent validation cohorts of paired clinical tissues to test our findings. Follow-up preclinical treatment strategies were evaluated in patient-derived xenografts. Results: We describe, in clinical samples, an archetype of rare ALDH1A1+ tumor cells that enrich and acquire AKT-mediated drug resistance in response to standard-of-care temozolomide (TMZ). Importantly, we observe that drug resistance of ALDH1A1+ cells is not intrinsic, but rather an adaptive mechanism emerging exclusively after TMZ treatment. In patient cells and xenograft models of disease, we recapitulate the enrichment of ALDH1A1+ cells under the influence of TMZ. We demonstrate that their subclonal progression is AKT-driven and can be interfered with by well-timed sequential rather than simultaneous antitumor combination strategy. Conclusions: Drug-resistant ALDH1A1+/pAKT+ subclones accumulate in patient tissues upon adaptation to TMZ therapy. These subclones may therefore represent a dynamic target in glioblastoma. Our study proposes the combination of TMZ and AKT inhibitors in a sequential treatment schedule as a rationale for future clinical investigation.
Association of Prediagnosis Obesity and Postdiagnosis Aspirin With Survival From Stage IV Colorectal Cancer
Authors: Jennifer S. Davis, Janelle C. Chavez, Melissa Kok, Yazmin San Miguel, Hwa Young Lee, Henry Henderson, Michael J. Overman, Van Morris, Bryan Kee, David Fogelman, Shailesh M. Advani, Benny Johnson, Christine Parseghian, John Paul Shen, Arvind Dasari, Kenna R. Shaw, Eduardo Vilar, Kanwal P. Raghav, Imad Shureiqi, Robert A. Wolff, Funda Meric-Bernstam, Dipen Maru, David G. Menter, Scott Kopetz, Shine Chang
Journal: JAMA Network Open (2022)

The potential relationship between obesity and colorectal cancer (CRC) outcome is poorly understood in patients with late-stage disease. Increased body mass index may negate aspirin use for cancer prevention, but its role as a factor on the effectiveness of postdiagnosis aspirin use is unclear.To evaluate how prediagnosis obesity and postdiagnosis aspirin use may be associated with overall survival in patients with late-stage colorectal cancer.This cross-sectional study used self-reported data from patients with metastatic or treatment-refractory disease who consented to a clinical protocol at MD Anderson Cancer Center, a large US cancer treatment center. Patients were enrolled between 2010 and 2018 and followed up for mortality through July 2020. Analyses were conducted through March 2022.Body mass index in the decade prior to initial diagnosis and regular aspirin use at survey completion.Overall survival was measured from stage IV diagnosis until death or last follow-up. Cox proportional hazards models were constructed to estimate associations of prediagnosis obesity and postdiagnosis aspirin use with overall survival.Of 656 patients included in this analysis, 280 (42.7%) were women, 135 (20.6%) were diagnosed with CRC before age 45 years, 414 (63.1%) were diagnosed between ages 45 and 65 years, and 107 (16.3%) were diagnosed at 65 years or older; 105 patients (16.0%) were Black or Hispanic, and 501 (76.4%) were non-Hispanic White. Controlling for age, sex, race, stage at initial diagnosis, and weight change between prediagnosis and survey date, patients with obesity in the decade prior to CRC diagnosis had significantly higher likelihood of death (hazard ratio, 1.45; 95% CI, 1.11-1.91) compared with those with normal prediagnosis body mass index. Furthermore, only patients with normal prediagnosis body mass index experienced significant survival benefit with postdiagnosis aspirin use (hazard ratio, 0.59; 95% CI, 0.39-0.90).In this cross-sectional study, our findings suggest potentially differential tumor development in the long-term physiologic host environment of obesity. Confirmation and further evaluation are needed to determine whether prediagnosis body mass index may be used to estimate the benefit from postdiagnosis aspirin use.
Colorectal Cancer Metastases in the Liver Establish Immunosuppressive Spatial Networking between Tumor-Associated <i>SPP1</i>+ Macrophages and Fibroblasts
Authors: Anuja Sathe, Kaishu Mason, Susan M. Grimes, Zilu Zhou, Billy T. Lau, Xiangqi Bai, Andrew Su, Xiao Tan, HoJoon Lee, Carlos J. Suarez, Quan Nguyen, George Poultsides, Nancy R. Zhang, Hanlee P. Ji
Journal: Clinical Cancer Research (2022)

Abstract Purpose: The liver is the most frequent metastatic site for colorectal cancer. Its microenvironment is modified to provide a niche that is conducive for colorectal cancer cell growth. This study focused on characterizing the cellular changes in the metastatic colorectal cancer (mCRC) liver tumor microenvironment (TME). Experimental Design: We analyzed a series of microsatellite stable (MSS) mCRCs to the liver, paired normal liver tissue, and peripheral blood mononuclear cells using single-cell RNA sequencing (scRNA-seq). We validated our findings using multiplexed spatial imaging and bulk gene expression with cell deconvolution. Results: We identified TME-specific SPP1-expressing macrophages with altered metabolism features, foam cell characteristics, and increased activity in extracellular matrix (ECM) organization. SPP1+ macrophages and fibroblasts expressed complementary ligand–receptor pairs with the potential to mutually influence their gene-expression programs. TME lacked dysfunctional CD8 T cells and contained regulatory T cells, indicative of immunosuppression. Spatial imaging validated these cell states in the TME. Moreover, TME macrophages and fibroblasts had close spatial proximity, which is a requirement for intercellular communication and networking. In an independent cohort of mCRCs in the liver, we confirmed the presence of SPP1+ macrophages and fibroblasts using gene-expression data. An increased proportion of TME fibroblasts was associated with the worst prognosis in these patients. Conclusions: We demonstrated that mCRC in the liver is characterized by transcriptional alterations of macrophages in the TME. Intercellular networking between macrophages and fibroblasts supports colorectal cancer growth in the immunosuppressed metastatic niche in the liver. These features can be used to target immune-checkpoint–resistant MSS tumors.
Participation of Older Adults in Clinical Trials for New Drug Applications and Biologics License Applications From 2010 Through 2019
Authors: S. W. Johnny Lau, Yue Huang, Julie Hsieh, Shenggang Wang, Qi Liu, Patricia W. Slattum, Janice B. Schwartz, Shiew-Mei Huang, Robert Temple
Journal: JAMA Network Open (2022)

Importance Older age may be accompanied by changes in the pharmacokinetics or pharmacodynamics or both of medications that can result in altered safety and efficacy profiles. Objective To assess representation of older adults in clinical trials of new drug applications (NDAs) and biologics license applications (BLAs). Design, Setting, and Participants This cross-sectional study analyzed US Food and Drug Administration (FDA) data for NDAs and BLAs approved from 2010 through 2019. Age distribution of clinical trial participants was compared with age distribution of the US population with the disease or disorder (prevalent population). Data were from adults enrolled in registration trials for depression, heart failure, insomnia, non–small cell lung cancer (NSCLC), nonvalvular atrial fibrillation (NVAF) stroke prevention, osteoporosis, and type 2 diabetes or adults sampled from US prevalent population in community-dwelling health data. Data were analyzed from November 2020 to February 2021. Exposures Trial enrollment. Main Outcomes and Measures Representativeness of trial populations was assessed by the participation to prevalence ratio (PPR) defined as the percentage of patients by age group among clinical trial participants to the percentage of patients by age group among US prevalent population. Results Data from 166 clinical trials (229 558 participants) for 44 NDAs and BLAs were analyzed. The most consistent finding was the limited enrollment of the oldest age groups, namely those 75 years and above for type 2 diabetes and NSCLC, and 80 years and above for NVAF stroke prevention, insomnia, heart failure, and osteoporosis. Adults aged 60 to 74 years were enrolled in equal or greater proportion than the US prevalent population. Conclusions and Relevance In this cross-sectional study, underrepresentation of the oldest adults existed during evaluation of new drugs and biologics, yet the older adults may represent significant proportions of the treatment population. Closing the representation gap between clinical trial enrollment and potential treatment populations is essential for safe and effective use of new drugs and biologics.
Association of Neighborhood Conditions and Resources for Children With Life Expectancy at Birth in the US
Authors: Kristen H. Shanahan, S. V. Subramanian, Kendall J. Burdick, Michael C. Monuteaux, Lois K. Lee, Eric W. Fleegler
Journal: JAMA Network Open (2022)

Importance To address inequities in life expectancy, we must understand the associations of modifiable socioeconomic and structural factors with life expectancy. However, the association of limited neighborhood resources and deleterious physical conditions with life expectancy is not well understood. Objective To evaluate the association of community social and economic conditions and resources for children with life expectancy at birth. Design, Setting, and Participants This cross-sectional study examined neighborhood child opportunity and life expectancy using data from residents of 65 662 US Census tracts in 2015. The analysis was conducted from July 6 to October 1, 2021. Exposures Neighborhood conditions and resources for children in 2015. Main Outcomes and Measures The primary outcome was life expectancy at birth at the Census tract level based on data from the US Small-Area Life Expectancy Estimates Project (January 1, 2010, to December 31, 2015). Neighborhood conditions and resources for children were quantified by Census tract Child Opportunity Index (COI) 2.0 scores for 2015. This index captures community conditions associated with children’s health and long-term outcomes categorized into 5 levels, from very low to very high opportunity. It includes 29 indicators in 3 domains: education, health and environment, and social and economic factors. Mixed-effects and simple linear regression models were used to estimate the associations between standardized COI scores (composite and domain-specific) and life expectancy. Results The study included residents from 65 662 of 73 057 US Census tracts (89.9%). Life expectancy at birth across Census tracts ranged from 56.3 years to 93.6 years (mean [SD], 78.2 [4.0] years). Life expectancy in Census tracts with very low COI scores was lower than life expectancy in Census tracts with very high COI scores (−7.06 years [95% CI, −7.13 to −6.99 years]). Stepwise associations were observed between COI scores and life expectancy. For each domain, life expectancy was shortest in Census tracts with very low compared with very high COI scores (education: β = −2.02 years [95% CI, −2.12 to −1.92 years]); health and environment: β = −2.30 years [95% CI, −2.41 to −2.20 years]; social and economic: β = −4.16 years [95% CI, −4.26 to −4.06 years]). The models accounted for 41% to 54% of variability in life expectancy at birth ( R 2 = 0.41-0.54). Conclusions and Relevance In this study, neighborhood conditions and resources for children were significantly associated with life expectancy at birth, accounting for substantial variability in life expectancy at the Census tract level. These findings suggest that community resources and conditions are important targets for antipoverty interventions and policies to improve life expectancy and address health inequities.
In Vitro Fertilization Outcomes After Inactivated COVID-19 Vaccine
Authors: Lisa M. Shandley, Heather S. Hipp
Journal: JAMA Network Open (2022)

Over the past 2.5 years, the global COVID-19 pandemic has killed millions of people worldwide, with consequences for every sector of the global economy, most notably, the health care system.Every medical specialty has been affected by the pandemic, including reproductive health care and assisted reproductive technology (ART).In the early, prevaccination days of the pandemic, resource scarcity
Association Between Time Interval from COVID-19 Vaccination to In Vitro Fertilization and Pregnancy Rate After Fresh Embryo Transfer
Authors: Wenhao Shi, Min Wang, Xia Xue, Na Li, Lijuan Chen, Juanzi Shi
Journal: JAMA Network Open (2022)

There is a lack of information regarding the need to postpone conception after COVID-19 vaccination.To investigate the time interval between the first dose of inactivated COVID-19 vaccine and in vitro fertilization (IVF) treatment as well as the rate of pregnancy after a fresh embryo transfer.This cohort study was conducted at a single public IVF center in China. Female patients aged 20 to 47 years and undergoing IVF treatment were consecutively registered from May 1 to December 22, 2021, with follow-up until March 31, 2022. Patients with SARS-CoV-2 infection before or during IVF treatment and those who underwent 2 or more IVF treatments, received the noninactivated or unknown COVID-19 vaccine, or did not have a fresh embryo transfer were excluded from this study.The vaccinated group (subdivided into 4 subgroups of time interval from first vaccination to fertilization treatment: ≤30 days, 31-60 days, 61-90 days, and ≥91 days) and nonvaccinated group.Risk ratios (RRs) for the association between the time interval and ongoing pregnancy (pregnancy continued at least 12 weeks).A total of 3052 female patients (mean [SD] age, 31.45 [3.96] years) undergoing IVF treatment were analyzed in this study. There were 667 vaccinated patients receiving IVF (35 were vaccinated ≤30 days, 58 were vaccinated 31-60 days, 105 were vaccinated 61-90 days, and 469 were vaccinated ≥91 days before fertilization treatment), and 2385 unvaccinated patients receiving treatment. The ovarian stimulation and laboratory parameters were similar among all groups. Ongoing pregnancy was significantly lower in the 30 days or less subgroup (34.3% [12 of 35]; adjusted RR [aRR], 0.61; 95% CI, 0.33-0.91) and the 31 to 60 days' subgroup (36.2% [21 of 58]; aRR, 0.63; 95% CI, 0.42-0.85). A slightly but not statistically lower rate was found in the 61 to 90 days' subgroup, and no reduced risk for ongoing pregnancy in the 91 days or more subgroup was observed (56.3% [264 of 469]; aRR, 0.96; 95% CI, 0.88-1.04) compared with the unvaccinated group (60.3% [1439 of 2385], as reference).Findings of this study suggest that receipt of the first inactivated COVID-19 vaccine dose 60 days or less before fertilization treatment is associated with a reduced rate of pregnancy. In patients undergoing IVF treatment with a fresh embryo transfer, the procedure may need to be delayed until at least 61 days after COVID-19 vaccination.
Prevalence of Online Sexual Offenses Against Children in the US
Authors: David Finkelhor, Heather Turner, Deirdre Colburn
Journal: JAMA Network Open (2022)

Importance Sexual abuse is increasingly facilitated by technology, but the prevalence and dynamics of such offenses have not been well delineated, making it difficult to design prevention strategies. Objective To examine the frequency and characteristics of online and technology-facilitated sexual abuse against children and youth. Design, Setting, and Participants In this nationally representative online survey study performed from November 19 to December 29, 2021, young adults aged 18 to 28 years were asked retrospectively about their childhood (&amp;amp;lt;18 years) experiences of online and technology-facilitated abuse. The 2639 participants were sampled from an online panel. Main Outcomes and Measures Participants were asked questions about 11 different kinds of online and technology-facilitated sexual abuse with follow-up questions about their dynamics and offenders. Prevalence rates were calculated for several cross-cutting concepts (online child sexual abuse, image-based sexual abuse, self-produced child sexual abuse images, nonconsensual sexting, online grooming by adults, revenge pornography, sextortion, and online commercial sexual exploitation). Survey weights were applied to obtain population prevalence estimates. Results A total of 2639 individuals (48.5% male, 49.8% female, and 1.8% other gender; 23.7% Hispanic, 12.6% non-Hispanic Black, 53.9% non-Hispanic White, 4.8% other race, and 5.0% ≥2 races) were surveyed. Childhood (before 18 years of age) prevalence rates were as follows: online child sexual abuse, 15.6% (SE, 1.0%); image-based sexual abuse, 11.0% (SE, 0.9%); self-produced child sexual abuse images, 7.2% (SE, 0.7%); nonconsensual sexting, 7.2% (SE, 0.7%); online grooming by adults, 5.4% (SE, 0.5%); revenge pornography, 3.1% (SE, 0.5%); sextortion, 3.5% (SE, 0.6%); and online commercial sexual exploitation, 1.7% (SE, 0.3%). The prime age of vulnerability across all categories was 13 to 17 years. Perpetrators in most categories were predominantly dating partners, friends, and acquaintances, not online strangers. Conclusions and Relevance The results of this national survey study suggest that a considerable portion of youth have experienced online child sexual abuse. Professionals planning prevention and intervention strategies for online sexual abuse should understand that dynamics include diverse episodes that are often extensions of dating abuse, sexual bullying, and sexual harassment, not only events perpetrated by adult internet predators.
Neighborhood Opportunity and Life Expectancy at Birth
Authors: Kelly R. Bergmann
Journal: JAMA Network Open (2022)

Kristen H. Shanahan, MD, MPH; S. V. Subramanian, PhD; Kendall J. Burdick, BA; Michael C. Monuteaux, ScD; Lois K. Lee, MD, MPH; Eric W. Fleegler, MD, MPH
Long-term life history predicts current gut microbiome in a population-based cohort study
Authors: Jiyeon Si, Jorge F. Vázquez-Castellanos, Ann C. Gregory, Lindsey Decommer, Leen Rymenans, Sebastian Proost, Javier Centelles Lodeiro, Martin Weger, Marlene Notdurfter, Christoph Leitner, Peter Santer, Gregorio Rungger, Johann Willeit, Peter Willeit, Raimund Pechlaner, Felix Grabherr, Stefan Kiechl, Herbert Tilg, Jeroen Raes
Journal: Nature Aging (2022)

Abstract Extensive scientific and clinical microbiome studies have explored contemporary variation and dynamics of the gut microbiome in human health and disease 1–3 , yet the role of long-term life history effects has been underinvestigated. Here, we analyzed the current, quantitative microbiome composition in the older adult Bruneck Study cohort (Italians, Bruneck, n = 304 (male, 154; female, 150); age 65–98 years) with extensive clinical, demographic, lifestyle and nutritional data collected over the past 26 years 4 . Multivariate analysis of historical variables indicated that medication history, historical physical activity, past dietary habits and specific past laboratory blood parameters explain a significant fraction of current quantitative microbiome variation in older adults, enlarging the explanatory power of contemporary covariates by 33.4%. Prediction of current enterotype by a combination of past and contemporary host variables revealed good levels of predictability (area under the curve (AUC), 0.78–0.83), with Prevotella and dysbiotic Bacteroides 2 being the best predicted enterotypes. These findings demonstrate long-term life history effects on the microbiota and provide insights into lifestyle variables and their role in maintaining a healthy gut microbiota in later life.
The dynseq browser track shows context-specific features at nucleotide resolution
Authors: Surag Nair, Arjun Barrett, Daofeng Li, Brian J. Raney, Brian T. Lee, Peter Kerpedjiev, Vivekanandan Ramalingam, Anusri Pampari, Fritz Lekschas, Ting Wang, Maximilian Haeussler, Anshul Kundaje
Journal: Nature Genetics (2022)
Signs of immunosenescence correlate with poor outcome of mRNA COVID-19 vaccination in older adults
Authors: Miguel Ángel Palacios-Pedrero, Janina M. Jansen, Cornelia Blume, Nils Stanislawski, Rebecca Jonczyk, Antonia Molle, Mariana Gonzalez Hernandez, Franziska K. Kaiser, Klaus Jung, Albert D. M. E. Osterhaus, Guus F. Rimmelzwaan, Giulietta Saletti
Journal: Nature Aging (2022)

Abstract Vaccination against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is effective in preventing COVID-19 hospitalization and fatal outcome. However, several studies indicated that there is reduced vaccine effectiveness among older individuals, which is correlated with their general health status 1,2 . How and to what extent age-related immunological defects are responsible for the suboptimal vaccine responses observed in older individuals receiving SARS-CoV-2 messenger RNA vaccine, is unclear and not fully investigated 1,3–5 . In this observational study, we investigated adaptive immune responses in adults of various ages (22–99 years old) receiving 2 doses of the BNT162b2 mRNA vaccine. Vaccine-induced Spike-specific antibody, and T and memory B cell responses decreased with increasing age. These responses positively correlated with the percentages of peripheral naïve CD4 + and CD8 + T cells and negatively with CD8 + T cells expressing signs of immunosenescence. Older adults displayed a preferred T cell response to the S2 region of the Spike protein, which is relatively conserved and a target for cross-reactive T cells induced by human ‘common cold’ coronaviruses. Memory T cell responses to influenza virus were not affected by age-related changes, nor the SARS-CoV-2-specific response induced by infection. Collectively, we identified signs of immunosenescence correlating with the outcome of vaccination against a new viral antigen to which older adults are immunologically naïve. This knowledge is important for the management of COVID-19 infections in older adults.